Pathogenic and targetable genetic alterations in 70 urachal adenocarcinomas.

Urachal cancer (UrC) is a rare but aggressive malignancy often diagnosed in advanced stages requiring systemic treatment. Although cytotoxic chemotherapy is of limited effectiveness, prospective clinical studies can hardly be conducted. Targeted therapeutic treatment approaches and potentially immunotherapy based on a biological rationale may provide an alternative strategy. We therefore subjected 70 urachal adenocarcinomas to targeted next-generation sequencing, conducted in situ and immunohistochemical analyses (including PD-L1 and DNA mismatch repair proteins [MMR]) and evaluated the microsatellite instability (MSI) status. The analytical findings were correlated with clinicopathological and outcome data and Kaplan-Meier and univariable/multivariable Cox regression analyses were performed. The patients had a mean age of 50 years, 66% were male and a 5-year overall survival (OS) of 58% and recurrence-free survival (RFS) of 45% was detected. Sequence variations were observed in TP53 (66%), KRAS (21%), BRAF (4%), PIK3CA (4%), FGFR1 (1%), MET (1%), NRAS (1%), and PDGFRA (1%). Gene amplifications were found in EGFR (5%), ERBB2 (2%), and MET (2%). We detected no evidence of MMR-deficiency (MMR-d)/MSI-high (MSI-h), whereas 10 of 63 cases (16%) expressed PD-L1. Therefore, anti-PD-1/PD-L1 immunotherapy approaches might be tested in UrC. Importantly, we found aberrations in intracellular signal transduction pathways (RAS/RAF/PI3K) in 31% of UrCs with potential implications for anti-EGFR therapy. Less frequent potentially actionable genetic alterations were additionally detected in ERBB2 (HER2), MET, FGFR1, and PDGFRA. The molecular profile strengthens the notion that UrC is a distinct entity on the genomic level with closer resemblance to colorectal than to bladder cancer.

Integrated 68Gallium Labelled Prostate-Specific Membrane Antigen-11 Positron Emission Tomography/Magnetic Resonance Imaging Enhances Discriminatory Power of Multi-Parametric Prostate Magnetic Resonance Imaging.

PURPOSE: To evaluate diagnostic accuracy of integrated 68Gallium labelled prostate-specific membrane antigen (68Ga-PSMA)-11 positron emission tomography (PET)/MRI in patients with primary prostate cancer (PCa) as compared to multi-parametric MRI. MATERIAL AND METHODS: A total of 22 patients with recently diagnosed primary PCa underwent clinically indicated 68Ga-PSMA-11 PET/CT for initial staging followed by integrated 68Ga-PSMA-11 PET/MRI. Images of multi-parametric magnetic resonance imaging (mpMRI), PET and PET/MRI were evaluated separately by applying Prostate Imaging Reporting and Data System (PIRADSv2) for mpMRI and a 5-point Likert scale for PET and PET/MRI. Results were compared with pathology reports of biopsy or resection. Statistical analyses including receiver operating characteristics analysis were performed to compare the diagnostic performance of mpMRI, PET and PET/MRI. RESULTS: PET and integrated PET/MRI demonstrated a higher diagnostic accuracy than mpMRI (area under the curve: mpMRI: 0.679, PET and PET/MRI: 0.951). The proportion of equivocal results (PIRADS 3 and Likert 3) was considerably higher in mpMRI than in PET and PET/MRI. In a notable proportion of equivocal PIRADS results, PET led to a correct shift towards higher suspicion of malignancy and enabled correct lesion classification. CONCLUSION: Integrated 68Ga-PSMA-11 PET/MRI demonstrates higher diagnostic accuracy than mpMRI and is particularly valuable in tumours with equivocal results from PIRADS classification.

Haematuria work-up in general care-A German observational study.

BACKGROUND: Haematuria is a common finding in the population and the diagnostic workflow of this symptom represents a large proportion of "work-load" in the urological outpatient clinic. AIMS: The intention of this study was to verify if the intensive diagnostic procedures of haematuria patients is justified by detection of a significant proportion of genito-urinary tract cancers. MATERIALS AND METHODS: In a retrospective design 1049 consecutive patients, who presented themselves with macro- or microhaematuria in the outpatient clinic PURR in the time from 2011 to 2012, were included in the study and the diagnostic procedures including ultrasound, intravenous urography, computed tomography of the abdomen and urethrocystoscopy as well as therapeutic consequences with its results were analysed. RESULTS: The study group comprised 570 women (54.3%) and 479 men (45.7%) with a median age of 58 years and macrohaematuria occurred in 89 patients. Diagnostics revealed seven patients with renal cell cancer, six patients with urothelial cell cancer of the renal pelvis, four patients with urothelial cell cancer of the ureter, 65 patients with urothelial cell cancer of the lower urinary tract and 17 patients with prostate cancer. Age, male gender and macrohaematuria were associated with a higher risk of cancer. CONCLUSIONS: The high incidence of urinary tract cancer in the data presented here support the rationale for diagnostic work-up of patients with micro- or macrohaematuria. Prospective randomised trials are necessary to identify index patients for second work-up after a primarily negative investigation as well as the role of molecular markers, which possibly enable to omit invasive work-up.

Soluble syndecan-1 (SDC1) serum level as an independent pre-operative predictor of cancer-specific survival in prostate cancer.

BACKGROUND: PSA-screening detects many cases of clinically non-aggressive prostate cancer (PC) leading to significant overtreatment. Therefore, pre-operatively available prognostic biomarkers are needed to help therapy decisions. Syndecan-1 (SDC1) is a promising prognostic tissue marker in several cancers including PC but serum levels of shedded SDC1-ectodomain (sSDC1) have not been assessed in PC. METHODS: A total of 150 patients with PC were included in this study (n = 99 serum samples, n = 103 paraffin-embedded samples (FFPE), n = 52 overlap). SDC1 protein expression and cellular localization was evaluated by immunohistochemistry (IHC), while sSDC1 serum concentrations were measured by ELISA. Serum sSDC1 levels were compared to those of MMP7, which is known to be a protease involved in SDC1 ectodomain-shedding. Clinico-pathological and follow-up data were collected and correlated with SDC1 tissue and serum levels. Disease (PC)-specific (DSS) and overall-survival (OS) were primary endpoints. RESULTS: Median follow-up was 167 months in the serum- and 146 months in the FFPE-group. SDC1-reactivity was higher in non-neoplastic prostate glands compared to PC. In addition, cytoplasmatic, but not membranous SDC1 expression was enhanced in PC patients with higher Gleason-score >6 PC (P = 0.016). Soluble SDC1-levels were higher in patients with Gleason-score >6 (P = 0.043) and metastatic disease (P = 0.022) as well as in patients with progressed disease treated with palliative transurethral resection (P = 0.002). In addition, sSDC1 levels were associated with higher MMP7 serum concentration (P = 0.005). In univariable analyses, only sSDC1-levels exhibited a trend to unfavorable DSS (P = 0.077). In a multivariable pre-operative model, high pre-operative sSDC1-level (>123 ng/ml) proved to be an independent marker of adverse OS (P = 0.048) and DSS (P = 0.020). CONCLUSIONS: The present study does not confirm the prognostic relevance of SDC1-IHC. The significant higher sSDC1 serum levels in advanced cases of PC, suggest that SDC1 shedding might be involved in PC progression. Additionally, high sSDC1-level proved to be an independent factor of adverse OS and DSS in a multivariable pre-operative model, making evaluation of sSDC1-levels a promising tool for pre-operative risk-stratification and/or therapy monitoring. Prostate 76:977-985, 2016. © 2016 Wiley Periodicals, Inc.

Circulating and Tissue Expression Levels of YKL-40 in Renal Cell Cancer.

PURPOSE: Blood levels of YKL-40 are elevated in various malignancies and other inflammatory diseases. Higher YKL-40 levels have consequently been shown to correlate with poor prognosis in several cancers. We investigated the prognostic value of circulating and tissue levels of YKL-40 in renal cell cancer. MATERIALS AND METHODS: Preoperative YKL-40 serum/plasma levels were determined in 222 surgically treated patients with renal cell cancer and in 35 controls. Postoperative serum samples were analyzed in 19 of the 222 renal cell cancer cases. Gene expression levels were assessed in 101 renal cell cancer frozen tissue samples using quantitative real-time reverse transcriptase-polymerase chain reaction. Finally immunohistochemical analysis was done in 37 renal cell cancer cases to assess tissue localization of YKL-40. Results were correlated with clinicopathological and followup data. RESULTS: YKL-40 serum but not tissue gene expression levels were higher in patients with renal cell cancer compared to controls (p = 0.050). Serum YKL-40 levels significantly increased following nephrectomy (p <0.001). High circulating YKL-40 concentrations were independently associated with shorter survival in the serum and plasma cohorts. YKL-40 gene expression did not correlate with patient prognosis. CONCLUSIONS: Preoperatively elevated circulating levels of YKL-40 predict survival in patients treated with nephrectomy for renal cell cancer independently of levels determined in serum or plasma. Tumor cells do not seem to be the main source of increased serum/plasma YKL-40 levels in patients with renal cell cancer.

Urachal Carcinoma of the Bladder: Impact of Clinical and Immunohistochemical Parameters on Prognosis.

PURPOSE: Urachal carcinoma of the bladder is a rare malignancy. Its histological phenotype is similar to that of primary bladder and colorectal adenocarcinoma. The aim of this study was to explore the expression and prognostic relevance of 6 select protein markers of urachal carcinoma of the bladder, including p53, Ki67, RHAMM, BGN, IMP3 and MMP-7, which were formerly shown to be prognostic in urothelial carcinoma and colorectal adenocarcinoma. MATERIALS AND METHODS: Clinical and followup data were obtained on a total of 26 patients with urachal carcinoma of the bladder treated at 2 university hospitals. Immunohistochemical analysis of p53, Ki67, RHAMM, BGN, IMP3 and MMP-7 expression was performed in samples from 15 patients. Clinicopathological parameters and immunohistochemical results were tested for prognostic value on univariable and multivariable analyses. RESULTS: Followup was 50 months. Five-year overall and progression-free survival was 46% and 32%, respectively. On multivariable analysis a positive resection margin was an independent predictor of poor overall survival (p = 0.025). RHAMM (p = 0.0431), IMP3 (p = 0.0052), Ki67 (p = 0.0006) and p53 (p = 0.0024) expression rates were significantly increased in urachal carcinoma of the bladder cells compared to normal urothelium. IMP3 was elevated in Sheldon tumor stage IIIA compared to IIIB or greater (p = 0.0048). None of the analyzed protein markers was associated with survival. CONCLUSIONS: The independent prognostic value of a positive resection margin underlines the importance of complete surgical removal of urachal carcinoma of the bladder combined with en bloc resection of the median umbilical ligament and umbilicus. Our results in a limited number of samples show that Ki67, p53, RHAMM and IMP3 expression is enhanced but has no prognostic significance in urachal carcinoma of the bladder.

Modified Preparation of the Neurovascular Bundle in Male to Female Transgender Patients.

INTRODUCTION: The main objective of gender reassignment surgery (GRS) in male to female (MtF) transgender people is to create a functional and aesthetic vagino-clitoral complex. Here we report on a modified preparation of the neurovascular bundle (NVB). MATERIALS AND METHODS: Between May 2011 and September 2014, 96 consecutive MtF transgender patients underwent GRS at our department. Sensitivity of the neoclitoris was assessed afterwards. Results were compared with a historical cohort from our department (2004-2010, n = 119) in which perioperative treatment was the same except for the preparation of the NVB. RESULTS: In 92 (95.8%) and 78 (81.2%) patients information on neoclitoral sensitivity was available and in 79 (82.3%) and 69 (71.9%) sensitivity was tested semiquantatively after first and second stage procedure respectively. A semiquantitative grading system correlated significantly with intermedium-term ability to achieve orgasms (p = 0.036). The modification led to a reduction in operation time by an average of 61 min. With the modified technique, we had a higher rate of postoperative local hematoma but with no need for further intervention. CONCLUSIONS: Preparation is safe and time saving both preserving the neoclitoral sensitivity and promoting a preferably feminine aspect of the mons pubis. Semiquantitative testing of sensitivity correlates with the intermedium-term capability of achieving orgasms.

Mistletoe Plant Extract in Patients with Nonmuscle Invasive Bladder Cancer: Results of a Phase Ib/IIa Single Group Dose Escalation Study.

PURPOSE: We determined the maximum tolerated dose, safety and effectiveness of intravesical instillation of mistletoe extract after transurethral resection of nonmuscle invasive bladder cancer. MATERIALS AND METHODS: In this single group dose escalation study patients with nonmuscle invasive bladder cancer were treated with weekly instillations of mistletoe extract for 6 weeks. Four weeks before instillation therapy all patients underwent transurethral resection of bladder tumors. During this procedure a marker tumor was left. At 12 weeks after the start of instillation therapy transurethral resection of the marker tumor or biopsy of the former marker tumor location was done so that patients were tumor free when entering followup until week 48. During the followup clinical assessment laboratory tests for safety and cystoscopy were done every 12 weeks. RESULTS: A total of 36 patients were treated with increasing doses of mistletoe extract. We found no dose limiting toxicity up to a dose of 675 mg of plant extract. Besides local reactions we saw hints that pyrexia may develop. All adverse events were well manageable. At 12 weeks a marker tumor remission rate of 55.6% (95% CI 38.1 to 72.1) was achieved. At 1 year a recurrence rate of 26.3% (95% CI 9.1 to 51.2) was observed. CONCLUSIONS: In this study intravesical instillation of mistletoe extract as treatment in patients with nonmuscle invasive bladder cancer was shown to be safe and well tolerated. Promising data on efficacy were observed and will be further investigated in a phase III study.

Renal cell carcinoma and tumour thrombus in the inferior vena cava: clinical outcome of 98 consecutive patients and the prognostic value of preoperative parameters.

OBJECTIVES: To evaluate the outcome of patients after nephrectomy and removal of tumour thrombus and to assess the prognostic value of preoperative parameters. PATIENTS AND METHODS: Ninety-eight patients who were surgically treated between 2002 and 2011 were included. Patients' charts were reviewed, and patients with renal cell carcinoma (RCC) and concomitant tumour thrombus in the renal vein (RV) were compared with those with extended inferior vena cava (IVC) thrombus. Wilcoxon rank-sum test, Kaplan-Meier analysis and uni- and multivariate Cox regression analysis were used for statistical evaluation. RESULTS: Follow-up was 36 months (20-122 months), and 5-year disease-specific survival (DSS) and overall survival were 68.4 and 54.1 %, respectively. Patients with extended thrombus (levels 2-4) had higher intraoperative transfusion rates of concentrated red cells (CRC) and fresh-frozen plasma (FFP) compared with patients with thrombus confined to the RV (CRC: 5.8 vs. 1.5, p < 0.0001; FFP: 2.3 vs. 0.4, p = 0.0032). Surgery time (190 vs. 107 min, p < 0.0001), duration of hospitalisation (16 vs. 11 days, p = 0.0269), serum phosphate (3.64 vs. 3.29 mmol/l, p = 0.0369) and CRP levels (6.7 vs. 4.4 mg/dl, p = 0.0194) as well as aPTT were increased (33.7 vs. 29.6 s, p = 0.0059) in extended thrombus disease. In multivariate analysis, the presence of distant metastasis (p = 0.03) and lymphovascular invasion (p = 0.001), high platelet counts (p = 0.001) and high serum potassium levels (p = 0.032) proved to be independent prognostic factors. CONCLUSION: The surgical treatment of RCC with tumour thrombus in the RV or IVC has favourable results. Extended thrombus disease requires multidisciplinary approach. High serum potassium levels and platelet counts are associated with reduced DSS.

Prognostic value of tissue and circulating levels of IMP3 in prostate cancer.

Tissue levels of the oncofetal protein insulin-like growth factor 2 (IGF2) messenger RNA-binding protein 3 (IMP3) have been associated with poor prognosis in multiple human malignancies. However, its circulating levels have not yet been analyzed. Therefore, the aim of this study was to assess the prognostic value of both serum and tissue levels of IMP3 in prostate cancer (PC). IMP3 protein expression was analyzed in 124 PC and 13 benign prostate hyperplasia (BPH) patients using immunohistochemistry. Gene expression levels of IMP3 and its molecular target IGF2 were analyzed in 29 frozen and 26 paraffin-embedded PC tissues using real-time polymerase chain reaction and immunohistochemistry. Serum IMP3 levels were assessed in 94 PC and 20 BPH patients as well as in 20 controls using enzyme-linked immunosorbent assay. IMP3 immunostaining was present in 0% (0/13) of BPHs, 15% (15/101) of clinically localized PCs and 65% (15/23) of palliatively treated metastatic PCs (p < 0.001). Accordingly, serum IMP3 concentrations were significantly higher in PC compared to BPH patients which were higher than those in controls (p < 0.001 each). The highest concentrations were detected in metastatic PC patients (p = 0.036). In patients who underwent radical prostatectomy high IMP3 serum levels were independently associated with poor cancer-specific survival. IMP3 gene and protein expressions were not correlated with those of IGF2. In conclusion, we found enhanced IMP3 levels in tissue and serum samples of PC patients compared to non-PC men. Moreover, IMP3 was associated with metastasis and PC-specific survival. The tumor promoting effect of IMP3 appears to be independent from its regulatory role on IGF2 in PC.

Evaluation of the PET component of simultaneous [(18)F]choline PET/MRI in prostate cancer: comparison with [(18)F]choline PET/CT.

PURPOSE: The aim of this study was to evaluate the positron emission tomography (PET) component of [(18)F]choline PET/MRI and compare it with the PET component of [(18)F]choline PET/CT in patients with histologically proven prostate cancer and suspected recurrent prostate cancer. METHODS: Thirty-six patients were examined with simultaneous [(18)F]choline PET/MRI following combined [(18)F]choline PET/CT. Fifty-eight PET-positive lesions in PET/CT and PET/MRI were evaluated by measuring the maximum and mean standardized uptake values (SUVmax and SUVmean) using volume of interest (VOI) analysis. A scoring system was applied to determine the quality of the PET images of both PET/CT and PET/MRI. Agreement between PET/CT and PET/MRI regarding SUVmax and SUVmean was tested using Pearson's product-moment correlation and Bland-Altman analysis. RESULTS: All PET-positive lesions that were visible on PET/CT were also detectable on PET/MRI. The quality of the PET images was comparable in both groups. Median SUVmax and SUVmean of all lesions were significantly lower in PET/MRI than in PET/CT (5.2 vs 6.1, p<0.05 and 2.0 vs 2.6, p<0.001, respectively). Pearson's product-moment correlation indicated highly significant correlations between SUVmax of PET/CT and PET/MRI (R=0.86, p<0.001) as well as between SUVmean of PET/CT and PET/MRI (R=0.81, p<0.001). Bland-Altman analysis revealed lower and upper limits of agreement of -2.77 to 3.64 between SUVmax of PET/CT vs PET/MRI and -1.12 to +2.23 between SUVmean of PET/CT vs PET/MRI. CONCLUSION: PET image quality of PET/MRI was comparable to that of PET/CT. A highly significant correlation between SUVmax and SUVmean was found. Both SUVmax and SUVmean were significantly lower in [(18)F]choline PET/MRI than in [(18)F]choline PET/CT. Differences of SUVmax and SUVmean might be caused by different techniques of attenuation correction. Furthermore, differences in biodistribution and biokinetics of [(18)F]choline between the subsequent examinations and in the respective organ systems have to be taken into account.

Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide.

Wilson disease is caused by accumulation of Cu(2+) in cells, which results in liver cirrhosis and, occasionally, anemia. Here, we show that Cu(2+) triggers hepatocyte apoptosis through activation of acid sphingomyelinase (Asm) and release of ceramide. Genetic deficiency or pharmacological inhibition of Asm prevented Cu(2+)-induced hepatocyte apoptosis and protected rats, genetically prone to develop Wilson disease, from acute hepatocyte death, liver failure and early death. Cu(2+) induced the secretion of activated Asm from leukocytes, leading to ceramide release in and phosphatidylserine exposure on erythrocytes, events also prevented by inhibition of Asm. Phosphatidylserine exposure resulted in immediate clearance of affected erythrocytes from the blood in mice. Accordingly, individuals with Wilson disease showed elevated plasma levels of Asm, and displayed a constitutive increase of ceramide- and phosphatidylserine-positive erythrocytes. Our data suggest a previously unidentified mechanism for liver cirrhosis and anemia in Wilson disease.

Pudendal nerve block in HDR-brachytherapy patients: do we really need general or regional anesthesia?

PURPOSE: In male patients, the pudendal block was applied only in rare cases as a therapy of neuralgia of the pudendal nerve. We compared pudendal nerve block (NPB) and combined spinal-epidural anesthesia (CSE) in order to perform a pain-free high-dose-rate (HDR) brachytherapy in a former pilot study in 2010. Regarding this background, in the present study, we only performed the bilateral perineal infiltration of the pudendal nerve. METHODS: In 25 patients (71.8 ± 4.18 years) suffering from a high-risk prostate carcinoma, we performed the HDR-brachytherapy with the NPB. The perioperative compatibility, the subjective feeling (German school marks principle 1-6), subjective pain (VAS 1-10) and the early postoperative course (mobility, complications) were examined. RESULTS: All patients preferred the NPB. There was no change of anesthesia form necessary. The expense time of NPB was 10.68 ± 2.34 min. The hollow needles (mean 24, range 13-27) for the HDR-brachytherapy remained on average 79.92 ± 12.41 min. During and postoperative, pain feeling was between 1.4 ± 1.08 and 1.08 ± 1.00. A transurethral 22 French Foley catheter was left in place for 6 h. All patients felt the bladder catheter as annoying, but they considered postoperative mobility as more important as complete lack of pain. The subjective feeling was described as 2.28 ± 0.74. Any side effects or complications did not appear. CONCLUSIONS: Bilateral NPB is a safe and effective analgesic option in HDR-brachytherapy and can replace CSE. It offers the advantage of almost no impaired mobility of the patient and can be performed by the urologist himself. Using transrectal ultrasound guidance, the method can be learned quickly.

Severity of urinary incontinence of nursing home residents correlates with malnutrition, dementia and loss of mobility.

INTRODUCTION: The prevalence of urinary incontinence increases with age. Especially in nursing homes people often do not only suffer from incontinence, in addition they present comorbidities, i.e. dementia or loss of mobility. In this study we assessed the severity of urinary incontinence and comorbidities of nursing home residents. METHODS: We included 81 residents of nursing homes who underwent recordings of medical history, physical examination and ultrasound diagnostic of the urinary tract. Grading of urinary incontinence was assessed by the amount of pads used daily. Severity of immobility, dementia and malnutrition was assessed. Further examinations were urinalysis by dip stick and microbiological testing, geriatric depression scale, and QLQ-C30. RESULTS: We found incontinence at different degrees present at 67/81 (83%) of nursing home residents. We could show, that more severe incontinence correlated with worse nutritional status (r = 0.53, p < 0.0001), increase in demential symptoms (r = 0.37, p = 0.0012) and worse mobility r = 0.71, p < 0.0001). There was no correlation for the severity of urinary incontinence with the prevalence of diabetes, intake of diuretics or the presence of urinary tract infections. CONCLUSIONS: Worsening of nutritional status, cognitive function and mobility not only correlate with the prevalence but also with the severity of urinary incontinence.

Serum endostatin levels correlate with enhanced extracellular matrix degradation and poor patients' prognosis in bladder cancer.

Endostatin, the proteolytic fragment of collagen XVIII, is an inhibitor of angiogenesis and tumor growth. Interestingly, elevated circulating endostatin levels have been found to correlate with poor patients' prognosis in several cancers. The aim of this study was to assess the prognostic value of endostatin in bladder cancer (BC) and to gain insight into the mechanisms involved in its production. This retrospective study included a total of 337 patients with BC and 103 controls. Collagen XVIII gene expression was analyzed using real-time PCR (n = 82). Endostatin tissue localization was assessed by immunohistochemistry (n = 27). Endostatin serum (n = 87) and urine (n = 153) levels were determined by ELISA. In 12 cases, both serum and paraffinized tissue samples from the same patients were available. We found decreased collagen XVIII tissue expression and increased endostatin urine and serum concentration in samples of patients with BC compared to controls. High serum endostatin levels correlated with the presence of lymph node metastases and MMP-7 concentrations and were independently associated with poor metastasis-free and disease-specific survival. Immunohistochemical analysis revealed a strong endostatin staining in the wall of tumor associated blood vessels in superficial but not in muscle-invasive BCs. Based on these, we concluded that elevated endostatin levels in patients with BC are the consequence of enhanced extracellular matrix degradation and are independent from collagen XVIII expression. Furthermore, serum endostatin levels may provide prognostic information independent from histopathological parameters and may therefore help to optimize therapy decisions. Loss of endostatin expression in tumor associated blood vessels might represent an important step supporting tumor-induced angiogenesis.

High insulin-like growth factor mRNA-binding protein 3 (IMP3) protein expression is associated with poor survival in muscle-invasive bladder cancer.

UNLABELLED: What's known on the subject? and What does the study add? Insulin-like growth factor mRNA-binding protein 3 (IMP3) is an oncofetal protein found to be re-expressed in a series of human cancers including bladder cancer. In vitro analyses showed an invasion and proliferation promoting effect for IMP3. Further in vitro studies suggested that IMP3 is able to bind to the mRNAs of CD44 and insulin-like growth factor 2 (IGF2), enhancing their stability and expression. However, this molecular interaction has not yet been analysed in tumour samples. In the present study, we identified for the first time high IMP3 tissue protein expression as an independent predictor of poor patients' survival in muscle-invasive bladder cancer. Furthermore, there was no correlation between IMP3 and its molecular targets in bladder carcinoma specimens and concluded that the tumour-promoting effect of IMP3 is not related to its regulatory action on IGF2 and CD44. OBJECTIVE: To assess the prognostic value and molecular actions of the oncofetal protein insulin-like growth factor mRNA-binding protein 3 (IMP3) in muscle-invasive bladder cancer (BC). PATIENTS AND METHODS: IMP3 expression was analysed by immunohistochemistry, real-time polymerase chain reaction and Western blot analysis in 224 patients with BC. The molecular targets of IMP3; CD44, insulin-like growth factor 2 (IGF2) and its receptor the IGF1 receptor (IGF1-R) were also investigated. Expression levels were correlated with clinical follow-up data by using both univariate and multivariate Cox regression analyses. RESULTS: IMP3 mRNA and protein levels were significantly elevated in high-stage and high-grade muscle-invasive BC. In muscle-invasive BC IMP3 protein but not gene expression proved to be an independent predictor of disease-specific (hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.28-4.56, P = 0.004) and overall survival (HR 2.07, 95% CI 1.12-3.82, P = 0.020). The expression levels of IGF2 and CD44 showed no correlation with that of IMP3. CONCLUSIONS: High IMP3 protein levels may identify patients with BC at high risk of disease progression and may therefore select patients for a more intensive therapy or for a strict follow-up. Its high expression in high-grade bladder carcinoma cells makes IMP3 for an attractive target for therapy. The tumour promoting effect of IMP3 is independent from its regulatory action on IGF2 and CD44 expression.

Central venous port implantations via the cephalic vein applying an intravasal electrographic control of the catheter tip position: a single-center experience of 316 cases.

PURPOSE: The aim of this study was the analysis of the feasibility and complication rate of central venous port implantation with the surgical cut-down technique applying an intravasal electrographic control of the catheter tip position performed by urologists. PATIENTS AND METHODS: In the time from December 1999 to November 2010, implantation of 324 subcutaneously implanted venous port systems (NuPort-System) has been performed in 316 patients, 221 men (mean age 59.5 years, range 11-87 years) and 95 women (mean age 57.6 years, range 7-85 years). Two hundred and fifty-nine (79.9%) port systems were placed under electrographic control of the catheter tip position. Duration of procedure, long-term device function, and complications such as infections, occlusions, dislocations, and thrombosis were all retrospectively measured and recorded until removal of the device, patient's death or the last known recorded documentation. RESULTS: In total, 359 devices have been used in 348 surgical procedures, 324 implantations (90.25%), and 35 explantations (9.75%). Port systems were implanted using the cephalic vein in 275 patients (84.9%), and in 49 (15.1%), the subclavian vein was used for insertion of the catheter. Mean surgical implantation time was 38.8 min (15-85 min). The median follow-up was 490.6 days (range 2-2,568); 159,764 catheter days (mean, 234 days, range 2-2,604) were documented. Of 35 explanted devices, the explantation was necessary due to complications in 28 cases (8.6%) with infection n = 6 (1.9%, 0.037 per 1,000 catheter days), occlusion n = 8 (2.5%, 0.050 per 1,000 catheter days), dislocation n = 7 (2.2%, 0.044 per 1,000 catheter days), deep vein thrombosis of the upper extremity n = 6 (1.9%, 0.037 per 1,000 catheter days), and clotting n = 1 (0.3%, 0.006 per 1,000 catheter days). Premature catheter removal (<30d post-operatively) was required in 6 patients (1.9%, 0.037 per 1,000 catheter days) due to complications: 3 catheter dislocations/malfunctions (0.9%, 0.019 per 1,000 catheter days), one port related infection, one pocket port infection, and one deep vein thrombosis of the upper extremity (0.3%, 0.006 per 1,000 catheter days). CONCLUSIONS: The intra-atrial ECG techniques to judge correct tip positioning for central venous port implantations are simple and economical. The exact position can be determined intraoperatively. It can justify a delayed postoperative chest X-ray to confirm CVC line tip placement. Nevertheless, the procedure and handling of the device later on has to be performed with care in order to avoid infections and technical problems.

Elevated serum matrix metalloproteinase 7 levels predict poor prognosis after radical prostatectomy.

Elevated matrix metalloproteinase-7 (MMP-7) tissue expression and serum concentration have been shown to be associated with cancer progression and metastasis. The aim of our study was to assess the prognostic value of preoperative circulating MMP-7 levels in serum samples of patients with clinically localized prostate cancer. Furthermore, we compared the serum MMP-7 levels between patients with organ confined and metastatic prostate cancer. MMP-7 levels were measured in 93 patients with localized prostate cancer, 13 patients with distant bone metastasis and in sera of 19 controls using enzyme-linked immunosorbent assay. The results were compared to the clinical follow-up data. We did not find any significant difference in MMP-7 serum levels between patients and controls (p = 0.268). Circulating MMP-7 serum concentration was significantly elevated in patients with distant metastasis (p < 0.001). For the detection of distant prostate cancer metastasis, using a cut-off value of 3.7 ng/ml, a specificity of 69% and a sensitivity of 92% were observed. Multivariate analysis identified high MMP-7 serum concentration as an independent risk factor for prostate cancer-related death both in a preoperative and a postoperative model (p = 0.003 and 0.018, respectively). Furthermore, the evaluation of predictive models revealed that addition of serum MMP-7 levels to the preoperatively available predictors improves prognostic accuracy (the concordance index increased from 0.631 to 0.734 when MMP-7 was included). Based on these, we concluded that MMP-7 is a potential marker to identify patients with metastatic prostate cancer. In clinically localized prostate cancer, MMP-7 may provide independent prognostic information, thereby helping to optimize therapy decisions.

Regulatory BCL2 promoter polymorphism (-938C>A) is associated with adverse outcome in patients with prostate carcinoma.

Molecular markers predictive of prostate cancer prognosis are urgently needed. Overexpression of the antiapoptotic protein, Bcl-2, has repeatedly been shown to be associated with adverse outcome in this malignancy. We hypothesized that a regulatory BCL2 -938C>A promoter polymorphism, which significantly affects promoter activity and Bcl-2 expression in different malignancies, may influence survival. Reporter assays and electrophoretic mobility shift assays reveled that the -938C>A BCL2 promoter polymorphism significantly affects promoter activity and transcription factor binding in prostate cancer cells. Significantly higher BCL2 mRNA expression was observed in primary prostate carcinomas derived from patients with the AA, compared to CC, genotype. Survival analysis showed that the -938AA genotype was an independent, unfavorable prognostic factor for relapse-free survival in a primary cohort of 142 patients and in an independent replication cohort of 148 patients, with hazard ratios (HR) of 4.4 (95% CI, 1.3-15.1; p = 0.018) and 4.6 (95% CI, 1.5-14.2; p = 0.009). Furthermore, the -938AA genotype was independently associated with worse overall survival in the replication series, with a HR of 10.9 (95% CI, 1.2-99.3; p = 0.034). We conclude that the BCL2 -938C>A polymorphism is an independent predictor of relapse-free and overall survival in patients with prostate cancer. The BCL2 -938C>A polymorphism should be evaluated prospectively and may also have promise in assisting optimal patient choice for treatment with BCL2-targeted drugs already in evaluation for prostate cancer treatment.

Urinary matrix metalloproteinase-7 level is associated with the presence of metastasis in bladder cancer.

OBJECTIVE: • To assess the presence of matrix metalloproteinase (MMP)-7 in urine samples of patients with bladder cancer and to investigate the correlation between MMP-7 urine concentration and clinicopathological variables. PATIENTS AND METHODS: • The presence of MMP-7 in the urine of patients with bladder cancer was tested in 32 representative cases using immunoprecipitation followed by western blot analysis. • Urinary MMP-7 concentration levels were analyzed in 132 patients with bladder cancer and 96 controls using an enzyme-linked immunosorbent assay. RESULTS: • MMP-7 levels did not differ significantly between patients with localized bladder cancer and controls (P= 0.174). On the other hand, we detected a fourfold, significantly elevated MMP-7 concentration in urine samples of patients with bladder cancer with regional or distant metastasis (P= 0.003). • Using a threshold value of 6.88 ng/ml, determined by receiver-operating characteristic curve analysis, a specificity of 82% and a sensitivity of 78% were observed. • Western blot analysis revealed that the 55-kDa tissue inhibitor of metalloproteinase 1 complexed MMP-7 is the dominant form of urinary matrilysin. CONCLUSIONS: • MMP-7 is present in detectable amounts in the urine of patients with bladder cancer. Its concentrations are significantly elevated in patients with metastatic disease. • Determination of urinary matrilysin level could help to detect bladder cancer metastasis, and may therefore provide a more reliable prognosis and influence therapy decisions.